3.2. TFIIH and XP/CS Symptoms
Cockayne Syndrome (CS) is also an autosomal recessive disorder,
characterized by neurodegeneration and premature aging. Other CS
phenotypes include cerebellar atrophy and demyelination. There are
multiple proteins within the NER pathway that lead to CS, particularly
for the two initiation factors in TC-NER, CSB and CSA. Several mutations
in CSB or CSA have been shown to cause CS, but they do not lead to XP,
suggesting CS is specifically related to defective TC-NER activity
(Fousteri & Mullenders, 2008; Rapin et al., 2000). The mechanism of CS
is especially interesting and puzzling, because UV damage does not
directly occur in the brain and it is unknown to what extent failure to
repair bulky lesions in active genes in neuronal cells contributes to
the onset of CS. Alternatively, previous studies suggest that CS may be
caused by defective repair of oxidative damage and/or improper
expression of genes related to neuron development (Y. Wang et al.,
2014). Interestingly, a small number of mutations in the XPD gene are
associated with XP combined with CS (XP/CS) (Lehmann, 2001; Rapin et
al., 2000). If TC-NER deficiency plays a causative role in CS, these
XP/CS mutations in XPD may cause deficiency in both subpathways in NER.
The identified XP/CS mutations are located either within the conserved
helicase motif, or in the p44-interacting domain (Lehmann, 2001). Why
these mutations cause both XP and CS symptoms whereas the majority of
other XPD mutations lead to XP disease, but no CS, remains unclear.